Tumor necrosis factor (TNF)-like ligand 1A (TL1A) is a member of the TNF family of cytokines also known as TNFSF15. TL1A is the only known ligand for its receptor Death Receptor 3 (DR3) also known as TNFRSF25. TL1A expression on antigen presenting cells (monocytes, macrophages, dendritic cells) and DR3 expression on effector cells (T cells, NK and NKT cells) is highly dependent on pro-inflammatory conditions (Migone et al, 2002, Immunity 16(3):479-492; Prehn et al, 2004, Clin. Immunol. 112(1):66-77; Shih et al, 2009, Eur J Immunol 39(11):3239-3250). In vivo and in vitro evidence support a co-stimulatory role for the TL1A/DR3 pathway on T cells and in enhancing effector cell functions, inflammatory cell expansion and cytokine secretion. Further, this pathway has been implicated in the regulation of pathogenic Th1, Th2, and Th17 T-helper responses, and of NK and NK-T cell responses, in immune-mediated diseases (Papadakis et al, 2004, J Immunol 172(11):7002-7007; Prehn et al, 2004, Clin. Immunol. 112(1):66-77; Papadakis et al, 2005, J Immunol 174(8):4985-4990; Pappu et al, 2008, J Exp Med 205(5):1049-1062; Takedatsu et al, 2008, Gastroenterology 135(2):552-567).
Studies of DR3 or TL1A gene-deficient mice or mice treated with anti-TL1A antibodies demonstrate a role for this pathway in a number of autoimmune disease models, such as IBD, asthma, multiple sclerosis, and arthritis (see Meylan et al., 2008, Immunity 29(1):79-89; Pappu et al, 2008; Hsu and Viney, 2011, Mucosal Immun. 4(4):368-370).
Moreover, significant literature from studies involving nonclinical species and humans implicates TL1A most prominently in the pathophysiology of inflammatory bowel disease (IBD), such as, ulcerative colitis (UC) and Crohn's Disease (CD). That is, numerous genome-wide association studies have linked several polymorphisms of the TL1A gene to UC and CD in patient populations of Japanese, European, and Asian origin (Yamazaki et al, 2005. Hum Mol Genet 14(22):3499-3506; Barrett et al, 2008, Nat Genet 40(8):955-962; Kakuta et al, 2009, Hum Mol Genet 18(6):1089-1098; Jostins et al, 2012, Nature 491(7422):119-124; Yamazaki et al, 2013, Gastroenterology 144(4):781-788).
Additionally, human inflamed IBD tissues show high levels of TL1A and DR3 expression and several independent laboratories have demonstrated that antibody blockade of TL1A prevents or attenuates established gut inflammation in a number of murine IBD models (Bamias et al, 2003, J Immunol 171(9):4868-4874; Prehn et al, 2004; Bamias et al, 2006, Proc Natl Acad Sci USA 103(22):8441-8446; Takedatsu et al, 2008, Gastroenterology 135(2):552-567; Shih et al, 2009; Kamada et al, 2010, Inflamm Bowel Dis 16(4):568-575; Meylan et al, 2011, Immunol Rev 244(1):188-196; Taraban et al, 2011, Mucosal Immunol 4(2):186-196; Bamias et al, 2012, Dig Liver Dis. 44(1):30-36).
Although the exact cause of IBD, e.g., CD and UC, remains unclear, inhibition of pro-inflammatory cytokines and adhesion molecules have been shown to provide some therapeutic benefit. However, despite current medical therapy, most CD patients may ultimately require surgery, and, over time, repeated resections can result in short gut syndrome, ultimately committing the patient to life-long parenteral nutrition and its associated complications. Thus, there is a long-felt unmet need for more robust therapies for CD patients. Further, there is a long-felt unment need for novel therapeutics to treat or ameliorate IBD, including UC and CD, as well as to treat other TL1A-mediated diseases and conditions. The present invention meets these needs.